1. Field:
This disclosure is concerned generally with intravenous nutrition and specifically with the use of lipid combinations which, on hydrolysis, yield controlled amounts of both long and medium chain fatty acids.
2. Prior Art:
Among the most important goals of nutritional support during severe injury or sepsis are a reduction in net protein catabolism and an increase in protein synthesis, especially in those tissues concerned with wound healing and host defense mechanisms.
Usually during severe stress, regardless of the initiating cause, there is an important mobilization of amino nitrogen from skeletal muscle and connective tissue to support the synthesis of visceral and acute phase secretory proteins. This metabolic response results in the acceleration of protein degradation and an elevation of energy expenditure or, as used herein, hypercatabolism. In addition, muscle protein catabolism provides the precursors for oxidation of branched chain amino acids and the synthesis and release of alanine for hepatic metabolism as a gluconeogenic substrate. Urinary nitrogen excretion is often elevated and the organism suffers negative nitrogen balance. If the stress is persistent, the nitrogen losses will eventually deplete the body's protein pool and this hypercatabolism will compromise critical functions resulting in a progressive deterioration of lean body mass and multiple organ failure. There is no doubt about the importance of dietary amino acid administration during severe injury. But because of the close relationship between protein and energy metabolism, caloried intake can also modify the utilization of amino acids, spare nitrogen and support protein synthesis.
The sources of non-protein calories commonly used in total parenteral nutrition are dextrose solutions and long chain fatty acid triglyceride (LCT) emulsions composed of either soybean or safflower oil. However, there is increasing concern about the undesirable effects of excessive dextrose administration in critically ill patients. Insulin resistance limits glucose oxidation and promotes lipid biosynthesis increasing the production of CO.sub.2 and the risks of developing fatty liver. On the other hand some controversy persists concerning the utilization of long chain fatty acids during severe stress. Some investigators have suggested that the nitrogen sparing capacity of long chain triglyceride emulsions are due solely to the glycerol that the emulsions contain. In severe stress long chain fatty acids may have a reduced capacity to enter the mitochondria for .beta.-oxidation, some investigators have reported a reduction in muscle carnitine levels which assists their entry into the mitochondria.
In addition, intravenous diets in which long chain triglyceride emulsions contribute over 50% of nonprotein calorie intake have been associated with anergy to cutaneous antigens and T-lymphocyte dysfunction. Furthermore, critically ill patients receiving such diets are at increased risk of developing secondary complications.
These considerations have promoted the search for nonconventional energy sources that can be more easily utilized in injury. Medium chain triglycerides (MCT) formed from saturated fatty acid with chain lengths of 6-14 carbons have a unique metabolism that may be of importance during injury. They are metabolized more rapidly than long chain triglycerides because they do not require carnitine to enter into the mitochondria where they are used for .beta.-oxidation. Moreover, the deposition as fat is less during medium chain triglyceride infusions than during long chain triglyceride administration because they require an initial elongation to 16-18 carbon length chains. Their rapid utilization as an energy substrate and frequent generation of ketone bodies may represent an important mechanism to spare nitrogen and support protein synthesis during injury. Proposed enteral and parenteral applications for MCTs have been described by A. C. Bach and V. K. Babayan in "Medium-Chain Triglycerides: an Update", Am. J. Clin. Nutrition 36, pp. 950-962, November, 1982. Parenteral applicatons of MCT/LCT mixtures have been described by D. Sailer and M. Muller in "Medium Chain Triglycerides in Parenteral Nutrition", J. Parent. and Ent. Nutr., Vol. 5, No. 2, pp. 115-119 (1981). Toxicity to intravenous administration of large quantities of MCT has been reported. Intravenous administration in dogs has produced somnolence, vomiting, coma and death. Similar findings have also been observed in fed, but not fasted rats. The effects of such nutrition on the hypercatabolic mammal, however, have not been investigated in great detail to date. As used herein, the term hypercatabolic refers to a state of elevated energy expenditure in a mammal which, if uncorrected, results in detrimental protein catabolism. Such state may be caused by a variety of life-threatening conditions including surgical injury, trauma, infection and the like.
As disclosed below, we have examined various calorie sources for total parenteral nutrition (TPN) in burned rats. We have examined the significance of infusing in addition to a basal intake of dextrose and amino acids, 33% more calories as either dextrose or a commercially available long chain triglyceride emulsion (soybean oil), medium chain triglyceride emulsion or a structured lipid emulsion composed of 60% medium chain and 40% long chain triglycerides. We evaluated the effect of these diets on changes in body weight, nitrogen balance, lever nitrogen, serum glucose, .beta.-hydroxybutyrate, lactate and albumin concentrations. Whole body leucine kinetics and protein fractional synthetic rate in muscle and liver were determined by using a constant intravenous infusion of L-[1-.sup.14 C]leucine as a tracer. Quite surprisingly, we found that when certain lipid sources were included in the TPN studies, the mammals studies were significantly more anabolic than animals receiving the other intravenous diets. As measured by nitrogen and net leucine balance, rats infused with one of our controlled lipid sources were in significant positive balance. Using the same controlled lipid, the highest hepatic protein synthesis was obtained and, in addition, it was found that more than 60% of the test animals' total caloric requirements could be satisfied with that lipid source without impairment of the function of the animal's reticuloendothelial system (RES). Details of the controlled lipid sources and their uses are described below.